Acquired chemoresistance can lead to increased resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus

Abstract

Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV) against different malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies have demonstrated that VSV-based OVs are effective against the majority of tested human PDAC cell lines. However, some PDAC cell lines are resistant to VSV. PDAC is one of the deadliest types of human malignancies in part due to intrinsic or acquired chemoresistance. Here, we investigated how acquired chemoresistance impacts the efficacy of VSV-based OV therapy. Using an experimental evolution approach, we generated PDAC cell lines with increased resistance to gemcitabine and examined their responsiveness to oncolytic virotherapy. We found that gemcitabine-resistant PDAC cells become more resistant to VSV. The cross-resistance correlated with upregulated levels of a subset of interferon-stimulated genes, resembling the interferon-related DNA damage resistance signature (IRDS), often associated with resistance of cancer cells to chemotherapy and/or radiation therapy. Analysis of ten different PDAC cell lines showed that four PDAC cell lines most resistant to VSV were also highly resistant to gemcitabine, and they all displayed IRDS-like expression in our previous reports. Our study highlights a possible interaction between two different therapies that should be considered in the future for the development of rational treatment regimens.

Intertumoral heterogeneity impacts oncolytic vesicular stomatitis virus efficacy in mouse pancreatic cancer cells

“…As VSV-based OV therapy becomes a more commonly tested therapeutic option in clinical trials (Clinicaltrials.gov trials NCT01628640, NCT03120624, NCT04046445, NCT03865212, NCT03017820, and NCT03647163), it is necessary to better understand how the effectiveness of VSV-based OV therapy is affected by the chemoresistance status of cancer cells. It has been observed in our previous studies and others ( 48 , 55 , 57 , 66 ) that the level of chemotherapeutic drug resistance may correlate with the level of antiviral signaling in cancer cells. This phenomenon is important to consider when determining the best therapeutic regimen for cancer patients.…”

“…We have recently shown that some human PDAC cell lines, which acquire resistance to chemotherapeutical drugs, can also simultaneously develop resistance to OV therapy ( 48 ). In addition, although the analyses of 10 different human PDAC cell lines showed no statistically significant correlation between their resistance to gemcitabine and VSV, 4 PDAC cell lines most resistant to VSV were also among 5 PDAC cell lines most resistant to gemcitabine ( 48 ). The chemoresistance of PDACs is one of the major reasons for the poor survival outcomes of PDAC patients.…”

“…Moreover, a previous study showed that the transformation of immortalized human uroepithelial cells by 3-MC increases IFN-stimulated genes (ISGs) expression, including expression of well-known antiviral genes, such as 2′−5′ OAS and MxA ( 54 ). In general, there is a growing body of studies ( 55 – 57 ), including previous studies from our lab ( 58 ), suggesting that cancer cells may upregulate antiviral signaling pathways to confer protection against radiation therapy and chemotherapy. The high degree of DNA damage caused by 3-MC in the pancreas may have led to an upregulation of antiviral signaling in PANC02-Luc cells.…”

The duality of STAT2 mediated type I interferon signaling in the tumor microenvironment and chemoresistance

“…STAT2 and its associated ISGs are overexpressed in several chemoresistant cancer types. Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) cells and subsequent resistance to vesicular stomatitis virus (an oncolytic viral therapy) correlates with an accumulation of STAT1 and STAT2 as well as upregulation of a particular subset of ISGs: MX1, MX2, IFITM1, IFIT1, and IFI44 [ 59 ]. Interestingly, enhanced expression of these genes occurs without upregulation of IFN-α or IFN-β.…”

An Extensive Review on Preclinical and Clinical Trials of Oncolytic Viruses Therapy for Pancreatic Cancer

“…In a study ( 228 ), interrogated the VSV resistance in highly chemoresistant pancreatic cancer cell lines. They identified that upregulated interferon-stimulated genes cause VSV resistance in pancreatic cancer.…”